Advertisement

Polycystic Ovary Syndrome and Metabolic Syndrome

  • Anne-Marie Carreau
  • Marie-Hélène Pesant
  • Jean-Patrice BaillargeonEmail author
Chapter
Part of the Contemporary Endocrinology book series (COE)

Abstract

The polycystic ovary syndrome (PCOS) is a very common disorder with important short-term and long-term cardiometabolic consequences. Indeed, affected women manifest many clinical and biochemical features of the metabolic syndrome, putting them at increased risks for diabetes and other cardiometabolic comorbidities. In the past 30 years, the key role of insulin resistance in the pathogenesis of PCOS has been stressed and this common etiology between the two syndromes might account for their similarities. In fact, PCOS is considered a consequence of insulin resistance in the same way as the metabolic syndrome, and women at risk for PCOS are also subject to the development of the metabolic syndrome. Thus, this chapter will explore the relationships between the metabolic syndrome and PCOS.

Keywords

Polycystic ovary syndrome Metabolic syndrome Insulin resistance Obesity Cardiovascular diseases Diabetes mellitus Hypertension Dyslipidemia Sleep apnea 

References

  1. 1.
    March WA, Moore VM, Willson KJ, Phillips DIW, Norman RJ, Davies MJ. The prevalence of polycystic ovary syndrome in a community sample assessed under contrasting diagnostic criteria. Hum Reprod. 2010;25:544–51.  https://doi.org/10.1093/humrep/dep399.CrossRefPubMedGoogle Scholar
  2. 2.
    Dumesic DA, Oberfield SE, Stener-Victorin E, Marshall JC, Laven JS, Legro RS. Scientific statement on the diagnostic criteria, epidemiology, pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev. 2015;36:487–525.  https://doi.org/10.1210/er.2015-1018.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Legro RS, Arslanian SA, Ehrmann DA, Hoeger KM, Murad MH, Pasquali R, et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2013;98:4565–92.  https://doi.org/10.1210/jc.2013-2350.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Rotterdam ESHRE/ASRM-Sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19:41–7.CrossRefGoogle Scholar
  5. 5.
    Carreau A-M, Baillargeon J-P. PCOS in adolescence and type 2 diabetes. Curr Diab Rep. 2015;15:564.  https://doi.org/10.1007/s11892-014-0564-3.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Dunaif A, Segal KR, Shelley DR, Green G, Dobrjansky A, Licholai T. Evidence for distinctive and intrinsic defects in insulin action in polycystic ovary syndrome. Diabetes. 1992;41:1257–66.CrossRefGoogle Scholar
  7. 7.
    Dunaif A, Segal KR, Futterweit W, Dobrjansky A. Profound peripheral insulin resistance, independent of obesity, in polycystic ovary syndrome. Diabetes. 1989;38:1165–74.CrossRefGoogle Scholar
  8. 8.
    Lewy VD, Danadian K, Witchel SF, Arslanian S. Early metabolic abnormalities in adolescent girls with polycystic ovarian syndrome. J Pediatr. 2001;138:38–44.  https://doi.org/10.1067/mpd.2001.109603.CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Cree-Green M, Newcomer BR, Coe G, Newnes L, Baumgartner A, Brown MS, et al. Peripheral insulin resistance in obese girls with hyperandrogenism is related to oxidative phosphorylation and elevated serum free fatty acids. Am J Physiol Endocrinol Metab. 2015;308:E726–33.CrossRefGoogle Scholar
  10. 10.
    Cree-Green M, Bergman BC, Coe GV, Newnes L, Baumgartner AD, Bacon S, et al. Hepatic steatosis is common in adolescents with obesity and PCOS and relates to De Novo lipogenesis but not insulin resistance. Obesity (Silver Spring). 2016;24:2399–406.  https://doi.org/10.1002/oby.21651.CrossRefGoogle Scholar
  11. 11.
    Diamanti-Kandarakis E, Dunaif A. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocr Rev. 2012;33:981–1030.  https://doi.org/10.1210/er.2011-1034.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Baillargeon J-P. Use of insulin sensitizers in polycystic ovarian syndrome. Curr Opin Investig Drugs. 2005;6:1012–22.PubMedGoogle Scholar
  13. 13.
    Baillargeon J-P, Iuorno MJ, Nestler JE. Insulin sensitizers for polycystic ovary syndrome. Clin Obstet Gynecol. 2003;46:325–40.CrossRefGoogle Scholar
  14. 14.
    Huber-Buchholz MM, Carey DG, Norman RJ. Restoration of reproductive potential by lifestyle modification in obese polycystic ovary syndrome: role of insulin sensitivity and luteinizing hormone. J Clin Endocrinol Metab. 1999;84:1470–4.  https://doi.org/10.1210/jcem.84.4.5596.CrossRefPubMedGoogle Scholar
  15. 15.
    Nestler JE, Jakubowicz DJ. Lean women with polycystic ovary syndrome respond to insulin reduction with decreases in ovarian P450c17 alpha activity and serum androgens. J Clin Endocrinol Metab. 1997;82:4075–9.  https://doi.org/10.1210/jcem.82.12.4431.CrossRefPubMedGoogle Scholar
  16. 16.
    Dunaif A, Xia J, Book CB, Schenker E, Tang Z. Excessive insulin receptor serine phosphorylation in cultured fibroblasts and in skeletal muscle. A potential mechanism for insulin resistance in the polycystic ovary syndrome. J Clin Invest. 1995;96:801–10.  https://doi.org/10.1172/JCI118126.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Ek I, Arner P, Bergqvist A, Carlström K, Wahrenberg H. Impaired adipocyte lipolysis in nonobese women with the polycystic ovary syndrome: a possible link to insulin resistance? J Clin Endocrinol Metab. 1997;82:1147–53.  https://doi.org/10.1210/jcem.82.4.3899.CrossRefPubMedGoogle Scholar
  18. 18.
    Skov V, Glintborg D, Knudsen S, Jensen T, Kruse TA, Tan Q, et al. Reduced expression of nuclear-encoded genes involved in mitochondrial oxidative metabolism in skeletal muscle of insulin-resistant women with polycystic ovary syndrome. Diabetes. 2007;56:2349–55.  https://doi.org/10.2337/db07-0275.CrossRefPubMedGoogle Scholar
  19. 19.
    Willis D, Mason H, Gilling-Smith C, Franks S. Modulation by insulin of follicle-stimulating hormone and luteinizing hormone actions in human granulosa cells of normal and polycystic ovaries. J Clin Endocrinol Metab. 1996;81:302–9.  https://doi.org/10.1210/jcem.81.1.8550768.CrossRefPubMedGoogle Scholar
  20. 20.
    Nahum R, Thong KJ, Hillier SG. Metabolic regulation of androgen production by human thecal cells in vitro. Hum Reprod. 1995;10:75–81.CrossRefGoogle Scholar
  21. 21.
    Barbieri RL, Makris A, Randall RW, Daniels G, Kistner RW, Ryan KJ. Insulin stimulates androgen accumulation in incubations of ovarian stroma obtained from women with hyperandrogenism. J Clin Endocrinol Metab. 1986;62:904–10.  https://doi.org/10.1210/jcem-62-5-904.CrossRefPubMedGoogle Scholar
  22. 22.
    Nestler JE, Jakubowicz DJ, de Vargas AF, Brik C, Quintero N, Medina F. Insulin stimulates testosterone biosynthesis by human thecal cells from women with polycystic ovary syndrome by activating its own receptor and using inositolglycan mediators as the signal transduction system. J Clin Endocrinol Metab. 1998;83:2001–5.  https://doi.org/10.1210/jcem.83.6.4886.CrossRefPubMedGoogle Scholar
  23. 23.
    Nelson-Degrave VL, Wickenheisser JK, Hendricks KL, Asano T, Fujishiro M, Legro RS, et al. Alterations in mitogen-activated protein kinase kinase and extracellular regulated kinase signaling in theca cells contribute to excessive androgen production in polycystic ovary syndrome. Mol Endocrinol. 2005;19:379–90.  https://doi.org/10.1210/me.2004-0178.CrossRefPubMedGoogle Scholar
  24. 24.
    Yki-Järvinen H, Mäkimattila S, Utriainen T, Rutanen EM. Portal insulin concentrations rather than insulin sensitivity regulate serum sex hormone-binding globulin and insulin-like growth factor binding protein 1 in vivo. J Clin Endocrinol Metab. 1995;80:3227–32.  https://doi.org/10.1210/jcem.80.11.7593430.CrossRefPubMedGoogle Scholar
  25. 25.
    Nestler JE, Powers LP, Matt DW, Steingold KA, Plymate SR, Rittmaster RS, et al. A direct effect of hyperinsulinemia on serum sex hormone-binding globulin levels in obese women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 1991;72:83–9.  https://doi.org/10.1210/jcem-72-1-83.CrossRefGoogle Scholar
  26. 26.
    Ciotta L, De Leo V, Farina M, Pafumi C, La Marca A, Cianci A. Endocrine and metabolic effects of insulin sensitizers in the treatment of patients with polycystic ovary syndrome and hyperinsulinaemia. Gynecol Obstet Invest. 2001;51:44–50. doi:52890CrossRefGoogle Scholar
  27. 27.
    Penna IAA, Canella PRB, Reis RM, Silva de Sá MF, Ferriani RA. Acarbose in obese patients with polycystic ovarian syndrome: a double-blind, randomized, placebo-controlled study. Hum Reprod. 2005;20:2396–401.  https://doi.org/10.1093/humrep/dei104.CrossRefPubMedGoogle Scholar
  28. 28.
    Baillargeon J-P, Carpentier A. Role of insulin in the hyperandrogenemia of lean women with polycystic ovary syndrome and normal insulin sensitivity. Fertil Steril. 2007;88:886–93.  https://doi.org/10.1159/000052890.CrossRefGoogle Scholar
  29. 29.
    Veldhuis JD, Strauss JF, Silavin SL, Kolp LA, Klase PA, Juchter D, et al. The role of cholesterol esterification in ovarian steroidogenesis: studies in cultured swine granulosa cells using a novel inhibitor of acyl coenzyme A: cholesterol acyltransferase. Endocrinology. 1985;116:25–30.  https://doi.org/10.1210/endo-116-1-25.CrossRefPubMedGoogle Scholar
  30. 30.
    Rosenfield RL, Ehrmann DA. The Pathogenesis of Polycystic Ovary Syndrome (PCOS): The hypothesis of PCOS as functional ovarian hyperandrogenism revisited. Endocr Rev. 2016;37:467–520.  https://doi.org/10.1210/er.2015-1104.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Vrbíková J, Cibula D, Dvoráková K, Stanická S, Sindelka G, Hill M, et al. Insulin sensitivity in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2004;89:2942–5.  https://doi.org/10.1210/jc.2003-031378.CrossRefPubMedGoogle Scholar
  32. 32.
    Morin-Papunen LC, Vauhkonen I, Koivunen RM, Ruokonen A, Tapanainen JS. Insulin sensitivity, insulin secretion, and metabolic and hormonal parameters in healthy women and women with polycystic ovarian syndrome. Hum Reprod. 2000;15:1266–74.CrossRefGoogle Scholar
  33. 33.
    Ciampelli M, Fulghesu AM, Cucinelli F, Pavone V, Caruso A, Mancuso S, et al. Heterogeneity in beta cell activity, hepatic insulin clearance and peripheral insulin sensitivity in women with polycystic ovary syndrome. Hum Reprod. 1997;12:1897–901.CrossRefGoogle Scholar
  34. 34.
    Baillargeon J-P, Jakubowicz DJ, Iuorno MJ, Jakubowicz S, Nestler JE. Effects of metformin and rosiglitazone, alone and in combination, in nonobese women with polycystic ovary syndrome and normal indices of insulin sensitivity. Fertil Steril. 2004;82:893–902.  https://doi.org/10.1016/j.fertnstert.2004.02.127.CrossRefPubMedGoogle Scholar
  35. 35.
    Baillargeon J-P, Nestler JE. Commentary: polycystic ovary syndrome: a syndrome of ovarian hypersensitivity to insulin? J Clin Endocrinol Metab. 2006;91:22–4.  https://doi.org/10.1210/jc.2005-1804.CrossRefPubMedGoogle Scholar
  36. 36.
    Lewis GF, Carpentier A, Adeli K, Giacca A. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr Rev. 2002;23:201–29.  https://doi.org/10.1210/edrv.23.2.0461.CrossRefGoogle Scholar
  37. 37.
    Trottier A, Battista M-C, Geller DH, Moreau B, Carpentier AC, Simoneau-Roy J, et al. Adipose tissue insulin resistance in peripubertal girls with first-degree family history of polycystic ovary syndrome. Fertil Steril. 2012;98:1627–34.  https://doi.org/10.1016/j.fertnstert.2012.08.025.CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Villa J, Pratley RE. Adipose tissue dysfunction in polycystic ovary syndrome. Curr Diab Rep. 2011;11:179–84.  https://doi.org/10.1007/s11892-011-0189-8.CrossRefPubMedGoogle Scholar
  39. 39.
    Wu Y, Zhang J, Wen Y, Wang H, Zhang M, Cianflone K. Increased acylation-stimulating protein, C-reactive protein, and lipid levels in young women with polycystic ovary syndrome. Fertil Steril. 2009;91:213–9.  https://doi.org/10.1016/j.fertnstert.2007.11.031.CrossRefPubMedGoogle Scholar
  40. 40.
    Velázquez ME, Bellabarba GA, Mendoza S, Sánchez L. Postprandial triglyceride response in patients with polycystic ovary syndrome: relationship with waist-to-hip ratio and insulin. Fertil Steril. 2000;74:1159–63.CrossRefGoogle Scholar
  41. 41.
    Vine DF, Wang Y, Jetha MM, Ball GD, Proctor SD. Impaired ApoB-Lipoprotein and Triglyceride Metabolism in Obese Adolescents With Polycystic Ovary Syndrome. J Clin Endocrinol Metab. 2017;102:970–82.  https://doi.org/10.1210/jc.2016-2854.CrossRefPubMedGoogle Scholar
  42. 42.
    Mai K, Bobbert T, Reinecke F, Andres J, Maser-Gluth C, Wudy SA, et al. Intravenous lipid and heparin infusion-induced elevation in free fatty acids and triglycerides modifies circulating androgen levels in women: a randomized, controlled trial. J Clin Endocrinol Metab. 2008;93:3900–6.  https://doi.org/10.1210/jc.2008-0714.CrossRefPubMedGoogle Scholar
  43. 43.
    Bellanger S, Battista M-C, Fink GD, Baillargeon J-P. Saturated fatty acid exposure induces androgen overproduction in bovine adrenal cells. Steroids. 2012;77:347–53.  https://doi.org/10.1016/j.steroids.2011.12.017.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Leblanc S, Battista M-C, Noll C, Hallberg A, Gallo-Payet N, Carpentier AC, et al. Angiotensin II type 2 receptor stimulation improves fatty acid ovarian uptake and hyperandrogenemia in an obese rat model of polycystic ovary syndrome. Endocrinology. 2014;155:3684–93.  https://doi.org/10.1210/en.2014-1185.CrossRefPubMedGoogle Scholar
  45. 45.
    Kriketos AD, Greenfield JR, Peake PW, Furler SM, Denyer GS, Charlesworth JA, et al. Inflammation, insulin resistance, and adiposity: a study of first-degree relatives of type 2 diabetic subjects. Diabetes Care. 2004;27:2033–40.CrossRefGoogle Scholar
  46. 46.
    Legro RS, Driscoll D, Strauss JF, Fox J, Dunaif A. Evidence for a genetic basis for hyperandrogenemia in polycystic ovary syndrome. Proc Natl Acad Sci U S A. 1998;95:14956–60.CrossRefGoogle Scholar
  47. 47.
    Zhao H, Lv Y, Li L, Chen Z-J. Genetic studies on polycystic ovary syndrome. Best Pract Res Clin Obstet Gynaecol. 2016;37:56–65.  https://doi.org/10.1016/j.bpobgyn.2016.04.002.CrossRefPubMedGoogle Scholar
  48. 48.
    Baillargeon J-P, Carpentier AC. Brothers of women with polycystic ovary syndrome are characterised by impaired glucose tolerance, reduced insulin sensitivity and related metabolic defects. Diabetologia. 2007;50:2424–32.  https://doi.org/10.1007/s00125-007-0831-9.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Sam S, Legro RS, Essah PA, Apridonidze T, Dunaif A. Evidence for metabolic and reproductive phenotypes in mothers of women with polycystic ovary syndrome. Proc Natl Acad Sci U S A. 2006;103:7030–5.  https://doi.org/10.1073/pnas.0602025103.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Sam S, Legro RS, Bentley-Lewis R, Dunaif A. Dyslipidemia and metabolic syndrome in the sisters of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:4797–802.  https://doi.org/10.1210/jc.2004-2217.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Yildiz BO, Yarali H, Oguz H, Bayraktar M. Glucose intolerance, insulin resistance, and hyperandrogenemia in first degree relatives of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88:2031–6.  https://doi.org/10.1210/jc.2002-021499.CrossRefPubMedGoogle Scholar
  52. 52.
    Essah PA, Nestler JE. The metabolic syndrome in polycystic ovary syndrome. J Endocrinol Invest. 2006;29:270–80.  https://doi.org/10.1007/BF03345554.CrossRefPubMedGoogle Scholar
  53. 53.
    Grundy SM, Cleeman JI, Daniels SR, Donato KA, Eckel RH, Franklin BA, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735–52.  https://doi.org/10.1161/CIRCULATIONAHA.105.169404.CrossRefPubMedGoogle Scholar
  54. 54.
    Alberti KGMM, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009;120:1640–5.  https://doi.org/10.1161/CIRCULATIONAHA.109.192644.CrossRefPubMedGoogle Scholar
  55. 55.
    Apridonidze T, Essah PA, Iuorno MJ, Nestler JE. Prevalence and characteristics of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:1929–35.  https://doi.org/10.1210/jc.2004-1045.CrossRefPubMedGoogle Scholar
  56. 56.
    Glueck CJ, Papanna R, Wang P, Goldenberg N, Sieve-Smith L. Incidence and treatment of metabolic syndrome in newly referred women with confirmed polycystic ovarian syndrome. Metabolism. 2003;52(7):908–15.CrossRefGoogle Scholar
  57. 57.
    Dokras A, Bochner M, Hollinrake E, Markham S, Vanvoorhis B, Jagasia DH. Screening women with polycystic ovary syndrome for metabolic syndrome. Obstet Gynecol. 2005;106:131–7.  https://doi.org/10.1097/01.AOG.0000167408.30893.6b.CrossRefPubMedGoogle Scholar
  58. 58.
    Vrbíková J, Vondra K, Cibula D, Dvoráková K, Stanická S, Srámková D, et al. Metabolic syndrome in young Czech women with polycystic ovary syndrome. Hum Reprod. 2005;20(12):3328–32.CrossRefGoogle Scholar
  59. 59.
    Vural B, Caliskan E, Turkoz E, Kilic T, Demirci A. Evaluation of metabolic syndrome frequency and premature carotid atherosclerosis in young women with polycystic ovary syndrome. Hum Reprod. 2005;20:2409–13.  https://doi.org/10.1093/humrep/dei100.CrossRefPubMedGoogle Scholar
  60. 60.
    Ehrmann DA, Liljenquist DR, Kasza K, Azziz R, Legro RS, Ghazzi MN, et al. Prevalence and predictors of the metabolic syndrome in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2006;91:48–53.  https://doi.org/10.1210/jc.2005-1329.CrossRefPubMedGoogle Scholar
  61. 61.
    Sharma S, Majumdar A. Prevalence of metabolic syndrome in relation to body mass index and polycystic ovarian syndrome in Indian women. J Hum Reprod Sci. 2015;8(4):202–8.CrossRefGoogle Scholar
  62. 62.
    Moran LJ, Misso ML, Wild RA, Norman RJ. Impaired glucose tolerance, type 2 diabetes and metabolic syndrome in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2010;16:347–63.  https://doi.org/10.1093/humupd/dmq001.CrossRefPubMedGoogle Scholar
  63. 63.
    Álvarez-Blasco F, Botella-Carretero JI, San Millán JL, Escobar-Morreale HF. Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women. Arch Intern Med. 2006;166:2081.  https://doi.org/10.1001/archinte.166.19.2081.CrossRefPubMedGoogle Scholar
  64. 64.
    Faloia E, Canibus P, Gatti C, Frezza F, Santangelo M, Garrapa GGM, et al. Body composition, fat distribution and metabolic characteristics in lean and obese women with polycystic ovary syndrome. J Endocrinol Invest. 2004;27:424–9.  https://doi.org/10.1007/BF03345285.CrossRefPubMedGoogle Scholar
  65. 65.
    Attaoua R, Ait El Mkadem S, Radian S, Fica S, Hanzu F, Albu A, et al. FTO gene associates to metabolic syndrome in women with polycystic ovary syndrome. Biochem Biophys Res Commun. 2008;373:230–4.  https://doi.org/10.1016/j.bbrc.2008.06.039.CrossRefPubMedGoogle Scholar
  66. 66.
    Shroff R, Syrop CH, Davis W, Van Voorhis BJ, Dokras A. Risk of metabolic complications in the new PCOS phenotypes based on the Rotterdam criteria. Fertil Steril. 2007;88:1389–95.  https://doi.org/10.1016/j.fertnstert.2007.01.032.CrossRefPubMedGoogle Scholar
  67. 67.
    Gulcelik NE, Aral Y, Serter R, Koc G. Association of hypoadiponectinemia with metabolic syndrome in patients with polycystic ovary syndrome. J Natl Med Assoc. 2008;100:64–8.  https://doi.org/10.1016/S0027-9684(15)31176-7.CrossRefPubMedGoogle Scholar
  68. 68.
    Ezeh U, Yildiz BO, Azziz R. Referral bias in defining the phenotype and prevalence of obesity in polycystic ovary syndrome. J Clin Endocrinol Metab. 2013;98:E1088–96.  https://doi.org/10.1210/jc.2013-1295.CrossRefPubMedPubMedCentralGoogle Scholar
  69. 69.
    Rossi B, Sukalich S, Droz J, Griffin A, Cook S, Blumkin A, et al. Prevalence of metabolic syndrome and related characteristics in obese adolescents with and without polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93:4780–6.  https://doi.org/10.1210/jc.2008-1198.CrossRefPubMedPubMedCentralGoogle Scholar
  70. 70.
    Coviello AD, Sam S, Legro RS, Dunaif A. High prevalence of metabolic syndrome in first-degree male relatives of women with polycystic ovary syndrome is related to high rates of obesity. J Clin Endocrinol Metab. 2009;94:4361–6.  https://doi.org/10.1210/jc.2009-1333.CrossRefPubMedPubMedCentralGoogle Scholar
  71. 71.
    Lizneva D, Kirubakaran R, Mykhalchenko K, Suturina L, Chernukha G, Diamond MP, et al. Phenotypes and body mass in women with polycystic ovary syndrome identified in referral versus unselected populations: systematic review and meta-analysis. Fertil Steril. 2016;106:1510–1520.e2.  https://doi.org/10.1016/j.fertnstert.2016.07.1121.CrossRefPubMedGoogle Scholar
  72. 72.
    Yildiz BO, Knochenhauer ES, Azziz R. Impact of obesity on the risk for polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93:162–8.  https://doi.org/10.1210/jc.2007-1834.CrossRefPubMedGoogle Scholar
  73. 73.
    Barber TM, Golding SJ, Alvey C, Wass JAH, Karpe F, Franks S, et al. Global adiposity rather than abnormal regional fat distribution characterizes women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93:999–1004.  https://doi.org/10.1210/jc.2007-2117.CrossRefPubMedGoogle Scholar
  74. 74.
    Mannerås-Holm L, Leonhardt H, Kullberg J, Jennische E, Odén A, Holm G, et al. Adipose tissue has aberrant morphology and function in PCOS: enlarged adipocytes and low serum adiponectin, but not circulating sex steroids, are strongly associated with insulin resistance. J Clin Endocrinol Metab. 2011;96:E304–11.  https://doi.org/10.1210/jc.2010-1290.CrossRefPubMedGoogle Scholar
  75. 75.
    Jin CH, Yuk JS, Choi KM, Yi KW, Kim T, Hur JY, et al. Body fat distribution and its associated factors in Korean women with polycystic ovary syndrome. J Obstet Gynaecol Res. 2015;41:1577–83.  https://doi.org/10.1111/jog.12767.CrossRefPubMedGoogle Scholar
  76. 76.
    Dolfing JG, Stassen CM, van Haard PMM, Wolffenbuttel BHR, Schweitzer DH. Comparison of MRI-assessed body fat content between lean women with polycystic ovary syndrome (PCOS) and matched controls: less visceral fat with PCOS. Hum Reprod. 2011;26:1495–500.  https://doi.org/10.1093/humrep/der070.CrossRefPubMedGoogle Scholar
  77. 77.
    Wild RA, Rizzo M, Clifton S, Carmina E. Lipid levels in polycystic ovary syndrome: systematic review and meta-analysis. Fertil Steril. 2011;95:1073-9.e1–11.  https://doi.org/10.1016/j.fertnstert.2010.12.027.CrossRefGoogle Scholar
  78. 78.
    Toulis KA, Goulis DG, Mintziori G, Kintiraki E, Eukarpidis E, Mouratoglou SA, et al. Meta-analysis of cardiovascular disease risk markers in women with polycystic ovary syndrome. Hum Reprod Update. 2011;17:741–60.  https://doi.org/10.1093/humupd/dmr025.CrossRefPubMedGoogle Scholar
  79. 79.
    Enkhmaa B, Anuurad E, Zhang W, Abbuthalha A, Kaur P, Visla J, et al. Lipoprotein(a) and apolipoprotein(a) in polycystic ovary syndrome. Clin Endocrinol (Oxf). 2016;84:229–35.  https://doi.org/10.1111/cen.12937.CrossRefGoogle Scholar
  80. 80.
    Berneis K, Rizzo M, Hersberger M, Rini GB, Di Fede G, Pepe I, et al. Atherogenic forms of dyslipidaemia in women with polycystic ovary syndrome. Int J Clin Pract. 2009;63:56–62.  https://doi.org/10.1111/j.1742-1241.2008.01897.x.CrossRefPubMedGoogle Scholar
  81. 81.
    Elting MW, Korsen TJM, Bezemer PD, Schoemaker J. Prevalence of diabetes mellitus, hypertension and cardiac complaints in a follow-up study of a Dutch PCOS population. Hum Reprod. 2001;16:556–60.CrossRefGoogle Scholar
  82. 82.
    Cõ R, Jirkovska A, La V, Platilova H, Zamrazil V. Cardiovascular risk factors in young Czech females with polycystic ovary syndrome. Hum Reprod. 2003;18:980–4.  https://doi.org/10.1093/humrep/deg218.CrossRefGoogle Scholar
  83. 83.
    Yu H-F, Chen H-S, Rao D-P, Gong J. Association between polycystic ovary syndrome and the risk of pregnancy complications: a PRISMA-compliant systematic review and meta-analysis. Medicine (Baltimore). 2016;95:e4863.  https://doi.org/10.1097/MD.0000000000004863.CrossRefGoogle Scholar
  84. 84.
    Holte J, Gennarelli G, Berne C, Bergh T, Lithell H. Elevated ambulatory day-time blood pressure in women with polycystic ovary syndrome: a sign of a pre-hypertensive state? Hum Reprod. 1996;11:23–8.CrossRefGoogle Scholar
  85. 85.
    Luque-Ramírez M, Alvarez-Blasco F, Mendieta-Azcona C, Botella-Carretero JI, Escobar-Morreale HF. Obesity is the major determinant of the abnormalities in blood pressure found in young women with the polycystic ovary syndrome. J Clin Endocrinol Metab. 2007;92:2141–8.  https://doi.org/10.1210/jc.2007-0190.CrossRefPubMedGoogle Scholar
  86. 86.
    Coviello AD, Legro RS, Dunaif A. Adolescent girls with polycystic ovary syndrome have an increased risk of the metabolic syndrome associated with increasing androgen levels independent of obesity and insulin resistance. J Clin Endocrinol Metab. 2006;91:492–7.  https://doi.org/10.1210/jc.2005-1666.CrossRefPubMedGoogle Scholar
  87. 87.
    Patel SS, Truong U, King M, Ferland A, Moreau KL, Dorosz J, et al. Obese adolescents with polycystic ovarian syndrome have elevated cardiovascular disease risk markers. Vasc Med. 2017;22(2):85–95.  https://doi.org/10.1177/1358863X16682107.CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Ollila M-ME, West S, Keinänen-Kiukaanniemi S, Jokelainen J, Auvinen J, Puukka K, et al. Overweight and obese but not normal weight women with PCOS are at increased risk of Type 2 diabetes mellitus—a prospective, population-based cohort study. Hum Reprod. 2017;32:423–31.  https://doi.org/10.1093/humrep/dew329.CrossRefPubMedPubMedCentralGoogle Scholar
  89. 89.
    Legro RS, Kunselman AR, Dodson WC, Dunaif A. Prevalence and predictors of risk for type 2 diabetes mellitus and impaired glucose tolerance in polycystic ovary syndrome: a prospective, controlled study in 254 affected women. J Clin Endocrinol Metab. 1999;84:165–9.  https://doi.org/10.1210/jcem.84.1.5393.CrossRefPubMedGoogle Scholar
  90. 90.
    Legro RS, Gnatuk CL, Kunselman AR, Dunaif A. Changes in glucose tolerance over time in women with polycystic ovary syndrome: a controlled study. J Clin Endocrinol Metab. 2005;90:3236–42.  https://doi.org/10.1210/jc.2004-1843.CrossRefPubMedGoogle Scholar
  91. 91.
    Boudreaux MY, Talbott EO, Kip KE, Brooks MM, Witchel SF. Risk of T2DM and impaired fasting glucose among PCOS subjects: results of an 8-year follow-up. Curr Diab Rep. 2006;6:77–83.CrossRefGoogle Scholar
  92. 92.
    Ehrmann DA, Barnes RB, Rosenfield RL, Cavaghan MK, Imperial J. Prevalence of impaired glucose tolerance and diabetes in women with polycystic ovary syndrome. Diabetes Care. 1999;22:141–6.CrossRefGoogle Scholar
  93. 93.
    Weerakiet S, Srisombut C, Bunnag P, Sangtong S, Chuangsoongnoen N, Rojanasakul A. Prevalence of type 2 diabetes mellitus and impaired glucose tolerance in Asian women with polycystic ovary syndrome. Int J Gynaecol Obstet. 2001;75:177–84.CrossRefGoogle Scholar
  94. 94.
    Talbott EO, Zborowski JV, Rager JR, Kip KE, Xu X, Orchard TJ. Polycystic ovarian syndrome (PCOS): a significant contributor to the overall burden of type 2 diabetes in women. J Womens Health (Larchmt). 2007;16:191–7.  https://doi.org/10.1089/jwh.2006.0098.CrossRefGoogle Scholar
  95. 95.
    Cowie CC, Rust KF, Ford ES, Eberhardt MS, Byrd-Holt DD, Li C, et al. Full accounting of diabetes and pre-diabetes in the U.S. population in 1988–1994 and 2005–2006. Diabetes Care. 2009;32:287–94.  https://doi.org/10.2337/dc08-1296.CrossRefPubMedPubMedCentralGoogle Scholar
  96. 96.
    Peppard HR, Marfori J, Iuorno MJ, Nestler JE. Prevalence of polycystic ovary syndrome among premenopausal women with type 2 diabetes. Diabetes Care. 2001;24:1050–2.CrossRefGoogle Scholar
  97. 97.
    Conn JJ, Jacobs HS, Conway GS. The prevalence of polycystic ovaries in women with type 2 diabetes mellitus. Clin Endocrinol (Oxf). 2000;52:81–6.CrossRefGoogle Scholar
  98. 98.
    Cussons AJ, Stuckey BGA, Watts GF. Cardiovascular disease in the polycystic ovary syndrome: new insights and perspectives. Atherosclerosis. 2006;185:227–39.  https://doi.org/10.1016/j.atherosclerosis.2005.10.007.CrossRefPubMedGoogle Scholar
  99. 99.
    Randeva HS, Tan BK, Weickert MO, Lois K, Nestler JE, Sattar N, et al. Cardiometabolic aspects of the polycystic ovary syndrome. Endocr Rev. 2012;33:812–41.  https://doi.org/10.1210/er.2012-1003.CrossRefPubMedPubMedCentralGoogle Scholar
  100. 100.
    Festa A, D’Agostino R, Howard G, Mykkänen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome: the Insulin Resistance Atherosclerosis Study (IRAS). Circulation. 2000;102:42–7.CrossRefGoogle Scholar
  101. 101.
    Haffner SM, Mykkänen L, Festa A, Burke JP, Stern MP. Insulin-resistant prediabetic subjects have more atherogenic risk factors than insulin-sensitive prediabetic subjects: implications for preventing coronary heart disease during the prediabetic state. Circulation. 2000;101:975–80.CrossRefGoogle Scholar
  102. 102.
    Sprung VS, Atkinson G, Cuthbertson DJ, Pugh CJA, Aziz N, Green DJ, et al. Endothelial function measured using flow-mediated dilation in polycystic ovary syndrome: a meta-analysis of the observational studies. Clin Endocrinol (Oxf). 2013;78:438–46.  https://doi.org/10.1111/j.1365-2265.2012.04490.x.CrossRefGoogle Scholar
  103. 103.
    Meyer ML, Malek AM, Wild RA, Korytkowski MT, Talbott EO. Carotid artery intima-media thickness in polycystic ovary syndrome: a systematic review and meta-analysis. Hum Reprod Update. 2012;18:112–26.  https://doi.org/10.1093/humupd/dmr046.CrossRefPubMedGoogle Scholar
  104. 104.
    Vryonidou A, Papatheodorou A, Tavridou A, Terzi T, Loi V, Vatalas I-A, et al. Association of hyperandrogenemic and metabolic phenotype with carotid intima-media thickness in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2005;90:2740–6.  https://doi.org/10.1210/jc.2004-2363.CrossRefPubMedGoogle Scholar
  105. 105.
    Shroff R, Kerchner A, Maifeld M, Van Beek EJR, Jagasia D, Dokras A. Young obese women with polycystic ovary syndrome have evidence of early coronary atherosclerosis. J Clin Endocrinol Metab. 2007;92:4609–14.  https://doi.org/10.1210/jc.2007-1343.CrossRefPubMedGoogle Scholar
  106. 106.
    Talbott EO, Zborowski JV, Rager JR, Boudreaux MY, Edmundowicz DA, Guzick DS. Evidence for an association between metabolic cardiovascular syndrome and coronary and aortic calcification among women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2004;89:5454–61.  https://doi.org/10.1210/jc.2003-032237.CrossRefPubMedGoogle Scholar
  107. 107.
    Talbott EO, Zborowski J, Rager J, Stragand JR. Is there an independent effect of polycystic ovary syndrome (PCOS) and menopause on the prevalence of subclinical atherosclerosis in middle aged women? Vasc Health Risk Manag. 2008;4:453–62.CrossRefGoogle Scholar
  108. 108.
    Christian RC, Dumesic DA, Behrenbeck T, Oberg AL, Sheedy PF, Fitzpatrick LA. Prevalence and predictors of coronary artery calcification in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88:2562–8.  https://doi.org/10.1210/jc.2003-030334.CrossRefPubMedGoogle Scholar
  109. 109.
    Orio F, Palomba S, Spinelli L, Cascella T, Tauchmanovà L, Zullo F, et al. The cardiovascular risk of young women with polycystic ovary syndrome: an observational, analytical, prospective case-control study. J Clin Endocrinol Metab. 2004;89:3696–701.  https://doi.org/10.1210/jc.2003-032049.CrossRefPubMedGoogle Scholar
  110. 110.
    Wang ET, Ku IA, Shah SJ, Daviglus ML, Schreiner PJ, Konety SH, et al. Polycystic ovary syndrome is associated with higher left ventricular mass index: The CARDIA Women’s Study. J Clin Endocrinol Metab. 2012;97:4656–62.  https://doi.org/10.1210/jc.2012-1597.CrossRefPubMedPubMedCentralGoogle Scholar
  111. 111.
    Yarali H, Yildirir A, Aybar F, Kabakçi G, Bükülmez O, Akgül E, et al. Diastolic dysfunction and increased serum homocysteine concentrations may contribute to increased cardiovascular risk in patients with polycystic ovary syndrome. Fertil Steril. 2001;76:511–6.CrossRefGoogle Scholar
  112. 112.
    Chang AY, Ayers C, Minhajuddin A, Jain T, Nurenberg P, de Lemos JA, et al. Polycystic ovarian syndrome and subclinical atherosclerosis among women of reproductive age in the Dallas heart study. Clin Endocrinol (Oxf). 2011;74:89–96.  https://doi.org/10.1111/j.1365-2265.2010.03907.x.CrossRefGoogle Scholar
  113. 113.
    de Groot PCM, Dekkers OM, Romijn JA, Dieben SWM, Helmerhorst FM. PCOS, coronary heart disease, stroke and the influence of obesity: a systematic review and meta-analysis. Hum Reprod Update. 2011;17:495–500.  https://doi.org/10.1093/humupd/dmr001.CrossRefPubMedGoogle Scholar
  114. 114.
    Shaw LJ, Bairey Merz CN, Azziz R, Stanczyk FZ, Sopko G, Braunstein GD, et al. Postmenopausal women with a history of irregular menses and elevated androgen measurements at high risk for worsening cardiovascular event-free survival: results from the National Institutes of Health–National Heart, Lung, and Blood Institute sponsored Women’s Ischemia Syndrome Evaluation. J Clin Endocrinol Metab. 2008;93:1276–84.  https://doi.org/10.1210/jc.2007-0425.CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Solomon CG, Hu FB, Dunaif A, Rich-Edwards JE, Stampfer MJ, Willett WC, et al. Menstrual cycle irregularity and risk for future cardiovascular disease. J Clin Endocrinol Metab. 2002;87:2013–7.  https://doi.org/10.1210/jcem.87.5.8471.CrossRefPubMedGoogle Scholar
  116. 116.
    Rocha ALL, Faria LC, Guimarães TCM, Moreira GV, Cândido AL, Couto CA, et al. Non – alcoholic fatty liver disease in women with polycystic ovary syndrome: systematic review and meta – analysis. J Endocrinol Invest. 2017;40(12):1279–88.  https://doi.org/10.1007/s40618-017-0708-9.CrossRefPubMedGoogle Scholar
  117. 117.
    Jacome-Sosa MM, Parks EJ. Fatty acid sources and their fluxes as they contribute to plasma triglyceride concentrations and fatty liver in humans. Curr Opin Lipidol. 2014;25:213–20.  https://doi.org/10.1097/MOL.0000000000000080.CrossRefPubMedGoogle Scholar
  118. 118.
    Sunny NE, Bril F, Cusi K. Mitochondrial adaptation in nonalcoholic fatty liver disease: novel mechanisms and treatment strategies. Trends Endocrinol Metab. 2017;28:250–60.  https://doi.org/10.1016/j.tem.2016.11.006.CrossRefPubMedGoogle Scholar
  119. 119.
    Belan M, Pelletier C, Baillargeon J-P. Alanine aminotransferase is a marker of lipotoxicity consequences and hyperandrogenemia in women with polycystic ovary syndrome. Metab Syndr Relat Disord. 2017;15(3):145–52.  https://doi.org/10.1089/met.2016.0119.CrossRefPubMedGoogle Scholar
  120. 120.
    Chen M-J, Chiu H-M, Chen C-L, Yang W-S, Yang Y-S, Ho H-N. Hyperandrogenemia is independently associated with elevated alanine aminotransferase activity in young women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2010;95:3332–41.  https://doi.org/10.1210/jc.2009-2698.CrossRefPubMedGoogle Scholar
  121. 121.
    Jie C, Chunhua W, Yi Z, Yuying W, Wendi X, Tzuchun L, et al. High free androgen index is associated with increased risk of non-alcoholic fatty liver disease in women with polycystic ovary syndrome, independently of obesity and insulin resistance. Int J Obes. 2017;49:1341–7.  https://doi.org/10.1038/ijo.2017.116.CrossRefGoogle Scholar
  122. 122.
    Vgontzas AN, Bixler EO, Chrousos GP. Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance. J Intern Med. 2003;254:32–44.CrossRefGoogle Scholar
  123. 123.
    Kahal H, Kyrou I, Tahrani AA, Randeva HS. Obstructive sleep apnoea and polycystic ovary syndrome: a comprehensive review of clinical interactions and underlying pathophysiology. Clin Endocrinol (Oxf). 2017;87:313–9.  https://doi.org/10.1111/cen.13392.CrossRefGoogle Scholar
  124. 124.
    Fogel RB, Malhotra A, Pillar G, Pittman SD, Dunaif A, White DP. Increased prevalence of obstructive sleep apnea syndrome in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2001;86:1175–80.  https://doi.org/10.1210/jcem.86.3.7316.CrossRefPubMedGoogle Scholar
  125. 125.
    Tasali E, Van Cauter E, Ehrmann DA. Polycystic ovary syndrome and obstructive sleep apnea. Sleep Med Clin. 2008;3:37–46.  https://doi.org/10.1016/j.jsmc.2007.11.001.CrossRefPubMedPubMedCentralGoogle Scholar
  126. 126.
    Tasali E, Van Cauter E, Hoffman L, Ehrmann DA. Impact of obstructive sleep apnea on insulin resistance and glucose tolerance in women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2008;93:3878–84.  https://doi.org/10.1210/jc.2008-0925.CrossRefPubMedPubMedCentralGoogle Scholar
  127. 127.
    Nandalike K, Agarwal C, Strauss T, Coupey SM, Isasi CR, Sin S, et al. Sleep and cardiometabolic function in obese adolescent girls with polycystic ovary syndrome. Sleep Med. 2012;13:1307–12.  https://doi.org/10.1016/j.sleep.2012.07.002.CrossRefPubMedPubMedCentralGoogle Scholar
  128. 128.
    Salley KES, Wickham EP, Cheang KI, Essah PA, Karjane NW, Nestler JE. POSITION STATEMENT: glucose intolerance in polycystic ovary syndrome—a position statement of the Androgen Excess Society. J Clin Endocrinol Metab. 2007;92:4546–56.  https://doi.org/10.1210/jc.2007-1549.CrossRefPubMedGoogle Scholar
  129. 129.
    Schroeder BM, American College of Obstetricians and Gynecologists. ACOG releases guidelines on diagnosis and management of polycystic ovary syndrome. Am Fam Physician. 2003;67:1619–20, 1622PubMedGoogle Scholar
  130. 130.
    American Association of Clinical Endocrinologists Polycystic Ovary Syndrome Writing Committee R, Futterweit W, Nestler J, Reaven G, Jellinger P, Handelsman Y, et al. American Association of Clinical Endocrinologists Position Statement on metabolic and cardiovascular consequences of polycystic ovary syndrome. Endocr Pract. 2005;11:126–34.  https://doi.org/10.4158/EP.11.2.125.CrossRefGoogle Scholar
  131. 131.
    Gagnon C, Baillargeon J-P. Suitability of recommended limits for fasting glucose tests in women with polycystic ovary syndrome. Can Med Assoc J. 2007;176:933–8.  https://doi.org/10.1503/cmaj.060607.CrossRefGoogle Scholar
  132. 132.
    Fauser BCJM, Tarlatzis BC, Rebar RW, Legro RS, Balen AH, Lobo R, et al. Consensus on women’s health aspects of polycystic ovary syndrome (PCOS). Hum Reprod. 2012;27:14–24.  https://doi.org/10.1093/humrep/der396.CrossRefGoogle Scholar
  133. 133.
    Teede HJ, Misso ML, Costello MF, Dokras A, Laven J, Moran L, Piltonen T, Norman RJ, International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Fertil Steril. 2018;110(3):364–79.CrossRefGoogle Scholar
  134. 134.
    Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393–403.  https://doi.org/10.1056/NEJMoa012512.CrossRefPubMedGoogle Scholar
  135. 135.
    Magkos F, Fraterrigo G, Yoshino J, Okunade AL, Patterson BW, Klein S, et al. Clinical and translational report effects of moderate and subsequent progressive weight loss on metabolic function and adipose tissue biology in humans with obesity clinical and translational report effects of moderate and subsequent progressive weight loss. Cell Metab. 2016:591–601.  https://doi.org/10.1016/j.cmet.2016.02.005.CrossRefGoogle Scholar
  136. 136.
    Weiss EP, Albert SG, Reeds DN, Kress KS, McDaniel JL, Klein S, et al. Effects of matched weight loss from calorie restriction, exercise, or both on cardiovascular disease risk factors: a randomized intervention trial. Am J Clin Nutr. 2016;104:576–86.  https://doi.org/10.3945/ajcn.116.131391.CrossRefPubMedPubMedCentralGoogle Scholar
  137. 137.
    Blair SN, Kohl HW, Paffenbarger RS, Clark DG, Cooper KH, Gibbons LW. Physical fitness and all-cause mortality. A prospective study of healthy men and women. JAMA. 1989;262:2395–401.CrossRefGoogle Scholar
  138. 138.
    Martin KA, Chang RJ, Ehrmann DA, Ibanez L, Lobo RA, Rosenfield RL, et al. Evaluation and treatment of hirsutism in premenopausal women: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008;93:1105–20.  https://doi.org/10.1210/jc.2007-2437.CrossRefPubMedGoogle Scholar
  139. 139.
    Watanabe RM, Azen CG, Roy S, Perlman JA, Bergman RN. Defects in carbohydrate metabolism in oral contraceptive users without apparent metabolic risk factors. J Clin Endocrinol Metab. 1994;79:1277–83.  https://doi.org/10.1210/jcem.79.5.7962320.CrossRefPubMedGoogle Scholar
  140. 140.
    Cagnacci A, Ferrari S, Tirelli A, Zanin R, Volpe A. Insulin sensitivity and lipid metabolism with oral contraceptives containing chlormadinone acetate or desogestrel: a randomized trial. Contraception. 2009;79:111–6.  https://doi.org/10.1016/j.contraception.2008.09.002.CrossRefPubMedGoogle Scholar
  141. 141.
    Cagnacci A, Ferrari S, Tirelli A, Zanin R, Volpe A. Route of administration of contraceptives containing desogestrel/etonogestrel and insulin sensitivity: a prospective randomized study. Contraception. 2009;80:34–9.  https://doi.org/10.1016/j.contraception.2009.01.012.CrossRefPubMedGoogle Scholar
  142. 142.
    Lidegaard Ø, Løkkegaard E, Jensen A, Skovlund CW, Keiding N. Thrombotic stroke and myocardial infarction with hormonal contraception. N Engl J Med. 2012;366:2257–66.  https://doi.org/10.1056/NEJMoa1111840.CrossRefPubMedGoogle Scholar
  143. 143.
    Baillargeon J-P, McClish DK, Essah PA, Nestler JE. Association between the current use of low-dose oral contraceptives and cardiovascular arterial disease: a meta-analysis. J Clin Endocrinol Metab. 2005;90:3863–70.  https://doi.org/10.1210/jc.2004-1958.CrossRefPubMedGoogle Scholar
  144. 144.
    Al Khalifah RA, Florez ID, Dennis B, Thabane L, Bassilious E. Metformin or oral contraceptives for adolescents with polycystic ovarian syndrome: a meta-analysis. Pediatrics. 2016;137:e20154089.  https://doi.org/10.1542/peds.2015-4089.CrossRefPubMedGoogle Scholar
  145. 145.
    Tang T, Norman RJ, Balen AH, Lord JM. Insulin-sensitising drugs (metformin, troglitazone, rosiglitazone, pioglitazone, D-chiro-inositol) for polycystic ovary syndrome. In: Tang T, editor. Cochrane database system review. Chichester, Wiley; 2003. p. CD003053.  https://doi.org/10.1002/14651858.CD003053.
  146. 146.
    Nesti L, Natali A. Metformin effects on the heart and the cardiovascular system: a review of experimental and clinical data. Nutr Metab Cardiovasc Dis. 2017;27:657–69.  https://doi.org/10.1016/j.numecd.2017.04.009.CrossRefPubMedGoogle Scholar
  147. 147.
    Costello MF, Shrestha B, Eden J, Johnson N, Moran LJ. Insulin-sensitising drugs versus the combined oral contraceptive pill for hirsutism, acne and risk of diabetes, cardiovascular disease, and endometrial cancer in polycystic ovary syndrome. In: Costello MF, editor. Cochrane database system review. Chichester: Wiley; 2007. p. CD005552.  https://doi.org/10.1002/14651858.CD005552.pub2.CrossRefGoogle Scholar
  148. 148.
    UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet. 1998;352:854–65.  https://doi.org/10.1016/S0140-6736(98)07037-8.CrossRefGoogle Scholar
  149. 149.
    Essah PA, Apridonidze T, Iuorno MJ, Nestler JE. Effects of short-term and long-term metformin treatment on menstrual cyclicity in women with polycystic ovary syndrome. Fertil Steril. 2006;86:230–2.  https://doi.org/10.1016/j.fertnstert.2005.12.036.CrossRefPubMedGoogle Scholar
  150. 150.
    Harborne L, Fleming R, Lyall H, Sattar N, Norman J. Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary syndrome. J Clin Endocrinol Metab. 2003;88:4116–23.  https://doi.org/10.1210/jc.2003-030424.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2020

Authors and Affiliations

  • Anne-Marie Carreau
    • 1
  • Marie-Hélène Pesant
    • 1
  • Jean-Patrice Baillargeon
    • 1
    Email author
  1. 1.Department of MedicineUniversité de SherbrookeSherbrookeCanada

Personalised recommendations